1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to carnitine analogs such as β-hydroxy-γ-aminophosphonates and β-amino-γ-aminophosphonates that inhibit carnitine acyltransferases, and intermediates, precursors, and derivatives thereof. In another embodiment, the invention relates to the use of β-hydroxy-γ-aminophosphonates and β-amino-γ-aminophosphonates, and analogs and derivatives thereof, for the treatment, amelioration or prevention of pathological conditions, diseases or disorders that are linked with fatty acid metabolism, such as non-insulin dependent diabetes or obesity. In another embodiment, the invention relates to methods for the preparation of β-hydroxy-γ-aminophosphonates, and intermediates, precursors, derivatives, and analogs thereof.
2. Related Art
L-carnitine, also known as levocarnitine or vitamin BT, is a cofactor that is present in tissues of animals, including humans, and serves several vital physiological roles. In particular, L-carnitine reacts with long chain fatty acids which cannot pass through the mitochondrial membrane. After such reaction, fatty acids are converted into membrane-permeable derivatives. In this pathway, L-carnitine plays a vital role for the utilization of fatty acids in mitochondria, via oxidation for the production of energy in eukaryotic organisms. This cofactor functions by binding activated fatty acids in the form of acyl carnitine (carnitine shuttle).
The use of L-carnitine in the treatment of hyperlipoproteinemia, hyperlipidemia, and myocardial dysfunction has been the subject of intense investigation (see, for example, Garazza, U.S. Pat. No. 4,255,449; Ramacci, U.S. Pat. No. 4,315,944; Siliprandi, Hypolipidemic Drugs, G. Ricci Ed.), New York; Raven, 1982; Pauly et al., Am. J. Kidney Dis. 41:S35-S43 (2003); Calvani et al., Basic Res. Cardiol. 95:75-83 (2000)). L-carnitine has also been reported to be useful as an adjuvant therapy in the management of renal anemia (Ciancuaruso, et al., Contrib. Nephrol. 137:426-430 (2002)). Certain carnitine analogs or derivatives have also been shown to have potential therapeutic value. For example, propionyl carnitine (the propionic ester of carnitine) has been shown to improve cardiac function (see, for example, Wiseman et al., Drugs Aging 12:243-248 (1998); Ferrari et al., Developments in Cardiovascular Medicine 162:323 (1995)). Acetyl carnitine has been proposed as a possible therapeutic agent for Alzheimer's disease (Pettegrew et al., Expert Review of Neurotherapeutics 2:647-654 (2002)). Bromoacetyl-L-carnitine has been shown in vitro to have a potent effect against T. Bruceli, a causative agent of African trypanosomiases (Gilbert et al., Biochem. Pharmacol. 32:3447-3451 (1983)). However, the potential therapeutic benefit of bromoacetyl-L-carnitine is limited because of toxicity due to metabolic release of bromine and/or bromoacetoacetate.
CPS 124, a carnitine monothiophosphate derivative which is a reversible and competitive inhibitor of carnitine palmitoyl transferase I, is reportedly undergoing clinical development for the treatment of non-insulin dependent diabetes mellitus (NIDDM) (Anderson, Curr. Pharm. Des. 4:1-16 (1998)). Nicotinyl carnitine derivatives have been studied as anticholesteremics and hypolipemics (Chibata et al., U.S. Pat. No. 4,032,641). Acylated aminocarnitines (Griffith, U.S. Pat. No. 4,781,863 and Giannessi et al., WO 2008/15081) have been studied as anticholesteremics and hypolipemics.
Carnitine acyltransferases are a group of structurally related enzymes involved in lipid catabolism. More specifically, these enzymes participate in fatty acid oxidation, catalyzing the exchange of acyl groups between carnitine and Coenzyme A (CoA) (Bieber, Ann. Rev. Biochem. 57:261-283 (1988); Kerner et al., Biochim. Biophys. Acta 1486:1-17 (2000); McGarry at al., Eur. Biochem. 244:1-14 (1997); Ramsay et al., Biochim. Biophys. Acta 1546:21-43 (2001)). Among the carnitine acyltransferases are carnitine acetyltransferase (CRAT, also known as CAT), carnitine octanoyltransferase (COT) and carnitine palmitoyltransferase (CPT), with substrate preferences for short-chain, medium-chain and long-chain fatty acids, respectively. These enzymes generally contain approximately 600 amino acid residues and have molecular weights of about 70 kD. They are the products of a multi-gene family which may have evolved by duplication of a single ancestral gene (van der Leij et al., Mol. Genet. Metab. 71:139-153 (2000)).
The physiologic relevance of carnitine acyltransferases not only is a source of pathology when these enzymes go awry, but also provides opportunities for treatment of diseases linked with disorders in fatty acid metabolism. The hyperglycemia found in diabetes results from decreased glucose disposal concomitant with increased glucose production, which are often associated with increased and uncontrolled fatty acid oxidation (Bebernitz et al., Curr Pharm. Des. 8:1199-1227 (2002)). Hence, inhibition of fatty acid oxidation has emerged as a new strategy for the treatment of diabetes (Bebernitz et al., Curr. Pharm. Des. 8:1199-1227 (2002); Wagman et al., Curr. Pharm. Des. 7:417-450 (2001)), in particular non-insulin dependent diabetes mellitus (“NIDDM”; also known as “mature onset diabetes”).
Thus, there exists a need for carnitine acyltransferase inhibitors for the treatment of diabetes, obesity, and other diseases that are associated with disorders in fatty acid metabolism. There also exists a need for pharmaceutical compositions comprising carnitine acyltransferase inhibitors. There also exists a need for a method of preparing carnitine acyltransferase inhibitors.